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Potassium Channel Linked to Schizophrenia

Scientists have connected a gene that regulates the flow of
potassium into and out of cells with schizophrenia. The discovery
provides a new potential therapeutic target.

Areas in the prefrontal cortex (right) and hippocampus
(left) where activity differed in healthy control subjects
during thinking tasks, depending on whether they had the
risk version of the KCNH2 potassium channel gene. Source:
NIMH.

Schizophrenia is a lifelong brain disorder that affects 1% of
adults worldwide. Symptoms, which begin in late adolescence or
early adulthood, include delusions such as hearing voices and
seeing hallucinations, paranoia and depression. Schizophrenia
affects attention, memory and organization.

It's unclear what causes schizophrenia. Studies suggest that
the disease stems from complex interactions between multiple
genes and environmental factors. Several candidate genes have
recently been statistically linked to the illness. Scientists
at NIH's National Institute of Mental Health (NIMH), National
Institute on Child Health and Human Development (NICHD) and their
European colleagues set out to follow these leads using 5 large
clinical data sets with hundreds of families. The research team
analyzed tiny variations called single nucleotide polymorphisms
(SNPs) that had already been linked to schizophrenia in previous
studies.

In the May 2009 edition of Nature Medicine, the researchers
reported that their analysis pinpointed 4 variations in a small
region of a gene called KCNH2. The KCNH2 gene encodes a potassium
channel, a type of protein that regulates the flow of potassium
ions into or out of cells. KCNH2 is best known for its role in
heart muscle, where it transports potassium ions out of cells,
recharging the muscle after each heartbeat to maintain a regular
rhythm.

In the brain, KCNH2 is known to be active primarily in the prefrontal
cortex and hippocampus. These areas are important for attention
and memory. In neurons, potassium channels help control when
the cells fire to signal neighboring neurons. The process is
partly regulated by the chemical messenger dopamine, which is
the main target of antipsychotic medications currently used to
treat schizophrenia.

The researchers discovered that healthy people who carried the
SNPs performed significantly worse on measures of IQ and mental
processing. MRI scans revealed that their brains had excessive
activity for the tasks being carried out—a phenomenon previously
implicated in schizophrenia. Healthy people with the SNPs also
had a smaller hippocampus, which has also been tied to schizophrenia.

Upon closer genetic analysis of the KCNH2 gene from 10 people
with schizophrenia, the researchers discovered a new form of
KCNH2, called Isoform 3.1. In healthy controls, the levels of
Isoform 3.1 and KCNH2 in the hippocampus were about the same.
However, the ratio of Isoform 3.1 to KCNH2 proved to be 2.5 higher
in people with schizophrenia.

The researchers used cultured rat neurons to reveal that Isoform
3.1 caused overactive neuron discharges. In the brain, the researchers
speculate, this could abnormally raise neuron and brain circuit
activity to cause the symptoms of schizophrenia.

The researchers say that a treatment designed to target Isoform
3.1 might improve information processing in the brains of people
with schizophrenia while avoiding heart-related side effects.